Glucagon like-peptide-1-(7,36)-amide (GLP-1) suppreses glucagon release and increases the early phase of insulin secretion. However, it is currently controversial as to whether GLP-1 alters insulin sensitivity. To address this question, we studied six subjects with type 2 diabetes mellitus on two occassions during which they were infused with either GLP-1 (1.2 pmol/Kg/Min) or normal saline. Insulin was infused to mimic the postprandial insulin concentrations typically observed in people with type 2 diabetes mellitus receiving GLP-1. Volunteers also received a glucose infusion in a pattern mimicking that which appears in the systemic circulation after ingestion of 50 g of carbohydrate. Overnight euglycemia was achieved by a variable insulin infusion prior to the study. Endogenous hormone secretion was inhibited by somatostatin infusion, basal growth hormone and glucagon were replaced so that their concentrations were identical on the two study days. A primed continuous infusion of 3-3H glucose was given to trace the glucose appearance and disappearance, and endogenous glucose production. Basal plasma glucose concentrations were identical (p=) on the two study days (5.2 +/- 0.5 vs. 5.4 +/- 0.2 mMol). Peak plasma glucose concentration and glycemic excursion on the GLP-1 day were identical to those achieved on the control day (p=) (5.2 +/- 0.5 vs. 5.4 +/- 0.2 mMol and 52 +/- 5 vs. 54 +/- 2 mMol over 6 hours). Endogenous glucose production and rates of glucose disappearance were also identical on the two study days (p=) (5.2 +/- 0.5 vs. 5.4 +/- 0.2 uMol/kg/min and 5.2 +/- 0.5 vs. 5.4 +/- 0.2 uMmol/kg/min respectively). We conclude that in the presence of identical insulin and glucagon concentrations, GLP-1 does not alter the ability of glucose and insulin to suppress glucose production and stimulate glucose effectiveness.